CORT118335 (miricorilant) is a selective glucocorticoid receptor (GR) modulator (SGRM) that is currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), based on strong efficacy in mouse models. We reveal gene-specific GR modulation by CORT118335 in the mouse liver. In cell-based models, we evaluated the biological activity of CORT118335 metabolites. Metabolite CORT118335-P9a showed potent GR agonism, while metabolite CORT118335-P9b was largely inactive. CORT118335-P9a concentrations in the mouse liver were very low, and therefore neither metabolite is likely to contribute to the beneficial effects of CORT118335 in vivo. We investigated various aspects of CORT118335 activity in reducing lipid levels in the mouse liver using a model of short-term high-fat diet feeding. Daily administration of CORT118335 appeared to lower hepatic triglyceride rapidly within several days after treatment initiation, specifically in male mice, and these effects were reversed after 7 days of treatment discontinuation. No synergy was observed between the lipid-lowering effects of CORT118335 and the TRβ agonist VK2809 or the PPARγ agonist pioglitazone. At a dose of 6 mg/kg/day, CORT118335 induced evident transcriptional effects with modest lowering of hepatic triglyceride levels, while higher doses induced a more pronounced lipid lowering but less ongoing transcriptional activity for hepatic lipid metabolism genes. Altogether we substantiate the potential of selective GR modulation using CORT118335 as a lipid-lowering strategy in MASLD and highlight the complexity of SGRM-mediated hepatic lipid lowering.
